High bioavailability and short dissolution times are desirable attributes of a pharmaceutical end product. Bioavailability is a term meaning the degree to which a pharmaceutical product, or drug, becomes available to the target tissue after being administered to the body. Poor bioavailability is a significant problem encountered in the development of pharmaceutical compositions, particularly those containing an active ingredient that is poorly soluble in water. For example, upon oral administration poorly water soluble drugs tend to be eliminated from the gastrointestinal tract before being absorbed into the circulation.
It is known that the rate of dissolution of a particulate drug can increase with increasing surface area, i.e., decreasing particle size. Consequently, efforts have been made to control the size and size range of drug particles in pharmaceutical compositions. For example, wet milling techniques have been used, as described in U.S. Pat. No. 5,145,684. However, such wet milling techniques exhibit problems associated with contamination from the grinding media. Moreover, exposing a drug substance to excessive mechanical shear or exceedingly high temperatures can cause the drug to change or lose activity due to decomposition of the active compound, or due to recrystallization processes, i.e., formation of different crystalline polymorphs or transformation, at least in part, from the crystalline to the amorphous state, as described by Florence et al, Effect of Particle Size Reduction on Digoxin Crystal Properties, Journal of Pharmaceutics and Pharmacology, Vol. 26, No. 6, 479-480 (1974), and R. Suryanarayanan and A. G. Mitchell, Evaluation of Two Concepts of Crystallinity Using Calcium Gluceptate as a Model Compound, International Journal of Pharmaceutics, Vol. 24, 1-17 (1985). In addition, wet milling techniques always result in the presence of a fraction of larger particles, which affects the time for the particles to completely dissolve.
Other efforts to reduce particle sizes include those such as described in U.S. Pat. Nos. 3,309,777 and 5,780,295. The '777 and '295 patents describes processes which include aerosolizing a biological suspension and impinging the aerosol particles onto a cold collecting surface, thereby encompassing each of the particles in a layer of pure water ice. The frozen aerosol particles are then removed from the cold surface and dried. The '777 and '295 patents teach the use of primarily water in the biological suspensions, which is not feasible when using poorly water soluble drug substances. Neither the '777 patent nor the '295 patent addresses the problems encountered when working with poorly water soluble drug substances.
Yet further efforts aimed at modifying particle structures are described in U.S. Pat. No. 3,932,943 and in WO 02/060411, which describe freezing materials by spraying those materials into a cryogenic liquid. However, the technologies described in these references have problems associated with recovering the particles from the cryogenic liquid, handling of the cryogenic liquid, and environmental issues.
U.S. Pat. Nos. 3,313,032 and 5,727,333 describe processes for drying materials from solution. However, neither of these patents address the need for improving the bioavailability and dissolution rates of poorly water soluble drug substances.
It would be an advantage to provide stable poorly water soluble pharmaceutical compositions in the micron or submicron particle size range which have improved bioavailability but do not have the problems associated with the above identified prior art.